How Antidepressants Work: A New View

Scientists at Oregon Health & Science University’s Vollum Institute have published a research article that describes a new view of how nerve cells communicate with each other. They believe their work will provide scientists with a better understanding of how antidepressants work in the human brain, hopefully leading to the development of better antidepressants with few or no side effects.

The article (“X-ray structure of dopamine transporter elucidates antidepressant mechanism”) in Nature came from the lab of Eric Gouaux, Ph.D., a senior scientist and a Howard Hughes Medical Institute Investigator. His team’s research focuses on the structure of the dopamine transporter, which helps regulate dopamine levels in the brain.

Dopamine is an essential neurotransmitter for the human body’s central nervous system; abnormal levels of dopamine are present in a range of neurological disorders including Parkinson’s disease, drug addiction, depression, and schizophrenia. Along with dopamine, the neurotransmitters noradrenaline and serotonin are transported by related transporters, which can be studied with greater accuracy based on the dopamine transporter structure.

The Gouaux lab’s more detailed view of the dopamine transporter structure better reveals how antidepressants act on the transporters and thus do their work.

“We present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 [angstroms] resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6, and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation,” wrote the investigators.

According to Dr. Gouaux, the more detailed view could help scientists and pharmaceutical companies develop drugs that do a much better job of targeting what they’re trying to target—and not create side effects caused by a broader blast at the brain proteins.

“By learning as much as possible about the structure of the transporter and its complexes with antidepressants, we have laid the foundation for the design of new molecules with better therapeutic profiles and, hopefully, with fewer deleterious side effects,” he said.